Our laboratory is engaged in investigating the behavioral concomittants of the inhibitory effects of galanin. The neuropeptide galanin is localized in the hippocampus, coexists with acetylcholine in the rat septohippocampal pathway, coexists with norepinephrine in the locus coeruleus, inhibits the release of glutamate, acetylcholine, serotonin, and norepinephrine, and inhibits evoked adeylate cyclase signal transduction. Galanin is overexpressed in the basal forebrain in Alzheimer's disease. Our past experiments revealed that central microinjection of galanin in rats impairs performance on several learning and memory tasks. We discovered that galanin overexpressing transgenic mice display analogous deficits on learning and memory tasks including the Morris water maze spatial learning probe trial, olfactory memory in social transmission of food preference, and trace cued fear conditioning, when compared to WT littermate controls. This year postdoctoral fellow Nathan Rustay tested the ability of a galanin receptor antagonist to rescue the memory deficits in galanin overexpressing transgenic mice. Intraventricular treatment with the peptidergic galanin antagonist M40 reversed the deficit on trace cued fear conditioning in galanin overexpressing transgenic mice. This finding supports the interpretation that the cognitive deficits in galanin transgenic mice are caused by the excess galanin peptide in the brain, not by some unknown compensatory mechanism. Further, translational indications are that a galanin receptor antagonist could rescue memory deficits in Alzheimer's patients. This year postdoctoral fellow Kathleen Bailey completed the first full behavioral phenotyping characterization of a new galanin subtype receptor GAL-R2 knockout mouse. The mutant line was generated by our collaborator Dr. John Hohmann at Nura, Inc. in Seattle. GAL-R2 knockout mice appeared normal on measures of general health, home cage behaviors, neurological reflexes, sensory abilities, and motor functions. GAL-R2 null mutants did not display deficits on trace fear conditioning or on spatial navigation in the Morris water maze. Dr. Bailey discovered an anxiogenic-like phenotype in GAL-R2 null mutants on the elevated plus maze. This finding supports the emerging evidence that galanin is an inhibitory neuromodulator with anxiolytic actions.